Alzheimer's disease (AD) is the most common dementia affecting millions of people. Although the etiology of the majority of AD cases remains unclear, epidemiological data indicate that exposure to environmental toxins such as pesticides increases the risk for developing AD. We have recently showed that exposure to pesticide paraquat exacerbated cognitive impairment and increased A accumulation in AD animal models and that overexpression of peroxiredoxin 3 (Prdx3), a mitochondrial antioxidant defense enzyme important for H2O2 removal, attenuated paraquat-induced cognitive impairment and A accumulation. Our results thus suggest that the increased risk of AD conferred by pesticide exposure is mediated by increased generation of mitochondrial reactive oxygen species (ROS). However, the mechanism of mitochondrial ROS in mediating cognitive impairment and A accumulation induced by paraquat exposure remains unclear. In this study, we will generate APP transgenic mice with overexpression of Prdx3, including APP transgenic mice with inducible overexpression of Prdx3 and APP transgenic mice with overexpression of Prdx3 in specific brain cell types such as neurons, astrocytes and microglia. We will then study the effects of paraquat exposure on cognition and amyloidogenesis in APP transgenic models with overexpression of Prdx3 and control APP transgenic mice. The data gathered will provide powerful evidence of the detailed mechanism of mitochondrial ROS in mediating paraquat- induced cognitive impairment and A accumulation. The overall hypothesis tested in this study is: Increased generation of mitochondrial ROS by neurons and glial cells plays a key role in mediating cognitive impairment and A accumulation induced by exposure to an environmental toxin. The hypothesis will be tested by three Specific Aims. Aim 1, to determine the long-term effects of paraquat exposure on cognition and A accumulation in AD mouse models with or without Prdx3 overexpression; Aim 2, to determine the effect of Prdx3 overexpression before or after paraquat exposure on attenuating paraquat-induced cognitive impairment and A accumulation; Aim 3, to determine the effect of Prdx3 overexpression specifically in neurons, astrocytes or microglia on attenuating paraquat-induced cognitive impairment and A accumulation. Our military service men and women are exposed to a variety of toxins such as pesticides during deployment, so the increased risk of AD conferred by exposure to toxins is a serious concern for the well-being of our military service men and women. The data gathered in this study will provide valuable information for developing preventive and therapeutic interventions to reduce the risk of AD conferred by toxin exposure, thereby benefitting our veterans.